Cost‐effectiveness of hepatitis C virus test‐and‐treat and risk reduction strategies among men who have sex with men living with HIV in France

Abstract Introduction Studies suggest that hepatitis C virus (HCV) micro‐elimination is feasible among men who have sex with men (MSM) living with human immunodeficiency virus (HIV), through treatment‐as‐prevention and interventions aimed at reducing risk behaviours. However, their economic impact is poorly understood. The aim of this study was to assess the cost‐effectiveness of HCV screening and risk reduction strategies in France. Methods A compartmental deterministic mathematical model was developed to describe HCV disease transmission and progression among MSM living with HIV in France. We evaluated different combinations of HCV screening frequency (every 12, 6 or 3 months) and risk reduction strategies (targeting only high‐risk or all MSM) from 2021 onwards. The model simulated the number of HCV infections, life‐expectancy (LYs), quality‐adjusted life‐expectancy (QALYs), lifetime costs and incremental cost‐effectiveness ratio (ICER) over a lifetime horizon (leading to an end of the simulation in 2065). Results All strategies increased QALYs, compared with current practices, that is yearly HCV screening, with no risk reduction. A behavioural intervention resulting in a 20% risk reduction in the high‐risk group, together with yearly screening, was the least expensive strategy, and, therefore, cost‐saving compared to current practices. The ICER per QALY gained for the strategy combining risk reduction for the high‐risk group with 6‐month HCV screening, compared to risk reduction with yearly screening, was €61,389. It also prevented 398 new HCV infections between 2021 and 2065, with a cost per infection averted of €37,790. All other strategies were dominated (more expensive and less effective than some other available alternative) or not cost‐effective (ICER per QALY gained > €100,000). Conclusions In the French context, current HCV screening practices without risk reduction among MSM living with HIV cannot be justified on economic grounds. Risk reduction interventions targeted to high‐risk individuals—alongside screening either once or twice a year—could be cost‐effective depending on the policymaker's willingness‐to‐pay.


I N T R O D U C T I O N
Since 2000, hepatitis C virus (HCV) has been an emerging epidemic among men who have sex with men (MSM) living with human immunodeficiency virus (HIV), especially in highincome countries [1,2]. Transmission of HCV in this population is associated with high-risk practices, such as unprotected traumatic sex, group sex and the use of drugs [3,4], especially the use of psychoactive substances in a sexual context (chemsex) [5].
The promise of highly effective and well-tolerated directacting antivirals (DAAs) [6] as a prevention tool has led the World Health Organization to issue the ambitious goal of HCV elimination by 2030 [7]. Micro-elimination-the reduction of HCV incidence to zero in targeted (high-risk) populations-could be a simple, low-cost, first step towards global elimination [8]. MSM living with HIV appear to be a suitable group for micro-elimination strategies because more than 80% of them are engaged in HIV care, where HCV monitoring is integrated. Moreover, growing awareness of HCV has recently led to more favourable conditions in France among this population, with a low prevalence of active HCV infection (1.8% in 2016 [9]) and declining primary incidence (from 0.98/100 person-years in 2014 to 0.45/100 person-years in 2017 [10]).
Access to care and rapid DAA treatment initiation (regardless of fibrosis stage) are universally available in France [11]. Intensified HCV screening, combined with immediate treatment, may prevent onward transmission (societal benefit) as well as HCV-related complications (individual benefit) [12]. Indeed, early detection facilitates rapid treatment initiation leading to reduced morbidity, mortality [13] and progression to costly complications [14]. However, uncertainties persist: the cost-effectiveness of more frequent HCV monitoringparticularly using costly polymerase chain reaction (PCR) tests (€54)-remains unproven; and DAA therapies are expensive.
Another key challenge is the reduction of risk behaviours for HCV infection [15]. Indeed, primary infection and reinfection rates among MSM who remain engaged in risky practices may particularly hamper the micro-elimination goal. Numerous studies evaluated risk reduction interventions for HIV and other sexually transmitted infections among MSM [16,17]. There are, however, major uncertainties regarding the potential effectiveness and related costs of HCV risk reduction in this population. Model-based analyses can inform better decisions by providing tools to assess the costs and benefits of such strategies.
The aim of the present study was to assist decisionmakers in allocating scarce resource by evaluating the costeffectiveness of different HCV screening strategies (followed by immediate treatment), and risk reduction strategies among MSM living with HIV in France. Outcomes of interest included life-expectancy (measured in life-years, LYs), quality-adjusted life-expectancy (measured in quality-adjusted life-years, QALYs) and healthcare costs.

Study design overview
We used a dynamic compartmental model. Lifetime horizon was considered, leading to an end of the simulation in 2065. All costs (in 2020 Euros €), LYs and QALYs were discounted at 2.5% per year over the first 30 years, decreasing to 1.5% thereafter [18]. We adopted a healthcare sector perspective, excluding indirect costs as recommended by the French National Authority for Health [18]. Our study population was the cohort of 67,950 French MSM living with HIV, from 2021. New individuals entered the model to take part in HCV transmission dynamics but were excluded from the economic evaluation.

Model description
We extended a previously published model of HCV transmission and liver disease progression among MSM living with HIV in France [12]. All individuals entered the model at the moment of HIV infection. Briefly, the states included HCV infection, HIV and HCV cascades of care (diagnosis, linkage to care and treatment), HCV disease progression and mortality (background, HIV related and HCV related). The target population was stratified into two risk groups (low-and high-risk) depending on whether or not individuals engaged in chemsex. The force of HCV infection was given by the product of: (1) group-specific transmission rates and (2) the time-dependent HCV prevalence. We assumed homogeneous mixing, that is no mixing preferences. We assigned a relative risk of HCV transmission for the high-risk group compared to the lowrisk group. Further model description and flow diagrams are available in Supplementary Material S1 and Figure S1. Model equations are provided in Supplementary Material S2.

Input parameters and model calibration
We obtained demographic and behavioural data from three main sources: (1) [21]. We used previous estimates [19,22] Table 1; the complete list is given in Table S1. The HCV transmission rate was calibrated via Approximated Bayesian Computation [24] to reflect decreasing HCV incidence rates observed over 2014-2017 in the ANRS CO4-FHDH [10] (Supplementary Material S3). Treatment eligibility criteria, treatment rates and sustained virological response (SVR) rates were varied between 2014 and 2019, reflecting changes in treatment practices and DAAs availability for MSM in France (Table  S2). Notably, national health insurance system data confirmed rapid treatment initiation after diagnosis (1 month) from 2019 [11].

Strategies
We defined 10 strategies from 2021, based on the frequency of HCV screening (every 12, 6 or 3 months) and the implementation of a risk reduction intervention leading to a 20% reduction in the risk of HCV acquisition ( Table 2). Reference scenario S1 represents current practices of yearly HCV screening, without risk reduction. S2 is the strategy currently recommended in France (6-month HCV screening) [28]. Strategies S3 and S4 represent more intensive screening (every 3 months) for the high-risk group or all MSM living with HIV. Strategies S5-S10 depict different combinations of screening and risk reduction. Two alternative risk reduction scenarios were presented, depending on the target population: high-risk group (S5, S7 and S9); or all MSM living with HIV, both low-and high-risk (S6, S8 and S10). We considered a theoretical risk reduction intervention based on educational counselling sessions that may result in a 20% risk reduction in HCV transmission at the population level. Since MSM living with HIV are usually followed-up yearly at the hospital, we defined a patient-centred risk reduction counselling intervention, to be delivered by hospital medical staff alongside annual consultation. We hypothesized that this would reduce HCV transmission at the population level by 20% [16,17,29], including those not in care. We assumed that counselling sessions lasted 1 hour during the first year of intervention (i.e. 2021) and 30 minutes thereafter. The 20% risk reduction target was attained progressively, starting at 0% and increasing linearly over the first 12 months, then sus-tained due to repeated annual counselling (i.e. no subsequent change in risk practices).

Costs
We included direct medical lifetime costs associated with HCV screening, that is testing (serological and PCR test) and diagnosis (initial check-up at HCV diagnosis), and HCV disease treatment and care. HCV costs stratified by disease stage were obtained from a study on healthcare consumption for chronic hepatitis C in France undertaken in 2010 [14]. Costs of HCV antiviral treatment were €24,935 or €25,750 for a 12-week DAA cure, with or without ribavirin. Given that our strategies are assumed to result in survival gains and that MSM living with HIV are mostly engaged in HIV care, we also included HIV healthcare costs (€17,529 per year) [30,31]. Staff costs for counselling were estimated from the hourly Every year 20% (high-risk) S1 + risk reduction (high-risk)

S6
Every year 20% (all) S1 + risk reduction (all) S7 Every 6 months 20% (high-risk) S2 + risk reduction (high-risk) S8 Every 6 months 20% (all) S2 + risk reduction (all) S9 Every 6 months (low-risk) Every 3 months (high-risk) 20% (high-risk) S3 + risk reduction (high-risk) S10 Every 3 months 20% (all) S4 + risk reduction (all) Note: Risk reduction strategies targeted to the high-risk population, that is chemsex practices (S5, S7 and S9), corresponded to a 20% decrease in the relative risk of HCV transmission for the high-risk group compared to the low-risk group. Risk reduction strategies for all MSM living with HIV (S6, S8 and S10) corresponded to a 20% decrease in the overall transmission rate.
wage for hospital nurses (€28). Supplementary Material S4 and Table S3 provide more details on costs.

Health-related quality-of-life
Estimates of health-related quality-of-life for individuals with HIV-HCV co-infection are scarce [32]. We, therefore, treated such losses as the sum of losses attributable to each condition alone (Table S4). We obtained health utility estimates for chronic hepatitis C from a 2014 to 2015 cross-sectional study of individuals with HCV mono-infection in France using the EuroQol-5D [33]. Estimates for cirrhosis complications were obtained from the Adelphi study [34]. Using a health utility estimate of 0.94 among individuals living with asymptomatic HIV from a meta-analysis published in 2002 [35], we assumed that HIV infection reduces the quality-of-life by 0.06 points. Health utilities were left unchanged during DAA treatment. We assumed that persons whose HCV infection was cleared to fibrosis stage F3 returned to the health utility of persons with HIV mono-infection (i.e. 0.94). Furthermore, health utility was increased after SVR for F4, as observed in Adelphi [34].

Model outcomes
The main outcome was the incremental cost-effectiveness ratio (ICER), measured in euros (€) per QALY gained. A strategy's ICER was defined as its additional cost divided by its additional QALY, when compared to the next-least-expensive strategy. In keeping with accepted practice, strategies were deemed to be dominated and excluded from ICER calculations if they resulted in higher costs but less (or equal) benefit, or had a higher ICER than a more effective strategy [36].
The French Health Authority has elected not to establish a willingness-to-pay (WTP) threshold to define a "cost-effective" intervention [18]. Accordingly, we report our results in terms of the greatest possible WTP for which an intervention might be considered cost-effective. As a complementary outcome, we report the number of infections and cost per infection averted.

Sensitivity analyses
We performed one-way deterministic sensitivity analyses to assess the robustness of our cost-effectiveness results in the face of input data uncertainty. Uncertainty intervals were either obtained from the literature or set to plausible ranges (Table S1). We considered risk reduction levels of 15% and 10% instead of 20%. Although recent studies assessing the efficacy of DAA therapy among individuals co-infected with HIV in real-world settings indicate SVR rates of 95% or less [37], we explored the impact of assuming a 98% SVR rate from 2019 for those treated in disease stages preceding cirrhosis. We performed an analysis with assortative mixing. We also conducted a probabilistic sensitivity analysis (PSA) (Table  S5), sampling 25,000 parameter sets and generating a costeffectiveness acceptability curve.

Main analysis
Strategies were sorted by increasing costs (  Compared to S5, increasing screening frequency every 6 months (S7) led to higher costs and QALYs with an ICER of €61,389/QALY. It also prevented 398 new HCV infections compared to S5, yielding a cost per infection averted of €37,790 (Table S6). From S7, the two subsequent nondominated strategies (S8, extending risk reduction to the lowrisk group; S10, intensifying screening every 3 months for all) yielded much higher ICERs (> €200,000/QALY), while preventing an additional 219-303 new HCV infections. All strategies without risk reduction intervention (S1-S4) were strictly dominated, that is more expensive and less effective than some other strategy, as were strategies targeting the high-risk group for intensive screening, that is every 3 months (S3, without risk reduction; or S9, with risk reduction). Figure 1 shows the efficiency frontier for the analysis on €/QALY gained. Any strategy on the efficiency frontier is labelled "efficient" (S5, S7, S8 and S10); strategies not on the frontier are labelled "dominated" (S1, S2, S3, S4 and S6).

Sensitivity analyses
Across broad variation in the underlying parameters, S5 and S7 remained on the efficient frontier, while intermediate strategies S2, S3, S4 and S6 remained dominated. Strategies S8 and S10 also remained on the frontier but produced ICERs > €200,000/QALY, exceeding what most observers would deem acceptable. Consequently, we focused our sensitivity analysis on the choice between S5 and S7, the two most policy-relevant strategies. Figure 2 presents the 10 parameters that produced the greatest variation in the ICER when comparing S7 and S5. The ICER strongly depended on the relative risk of HCV transmission for the high-risk group compared with the lowrisk group (ranging from €8378 to €120,909/QALY). Our results were also sensitive to the proportion of MSM in the high-risk group and the probability of spontaneous clearance; a proportion of 22% in the high-risk group and 25% of spontaneous clearance during acute infection both yielded

Figure 3. Results from the probabilistic sensitivity analysis. The cost-effectiveness acceptability curve depicts the probability that a given strategy is cost-effective (defined as achieving the maximum net monetary benefit [NMB]) as a function of the WTP threshold across all simulations of the probabilistic sensitivity analysis (PSA). The cost-effectiveness acceptability frontier, represented by black squares, displays the probability of the optimal strategy (defined as maximizing the expected benefit on average across all samples of the PSA at each WTP) to be cost-effective. In a few cases, strategies with the highest probability of being cost-effective did not necessarily
correspond with the optimal strategy, defined as having the highest expected net benefit in average, as shown by the cost-effectiveness acceptability frontier. For example, at a WTP threshold of €55,000/QALY, S7 had the highest expected net benefit (i.e. optimal strategy), but a slightly lower probability of being cost-effective than S5. Abbreviations: GDP, gross domestic product; WTP, willingness-to-pay.
an ICER of €96,000/QALY. S5 remained the cheapest strategy and was cost-saving compared with current practices even when the efficacy of risk reduction interventions was set to 10%. In this case, the ICER was €47,317/QALY for S7 compared to S5 (Table S7). Finally, S7 was less cost-effective at higher SVR rates and with assortative mixing, with ICERs of €77,338/QALY (Table S8) and €96,667/QALY compared to S5 (Table S9), respectively.
In PSA, at a WTP of €33,000/QALY (roughly the French Gross Domestic Product [GDP]), S5 was cost-effective in 80% of simulations, and S7 in 17% of simulations. S7 was cost-effective with a 75% probability at a WTP of roughly three times the GDP (i.e. €99,000) and remained the strategy with the highest probability of being costeffective when considering a WTP up to €200,000/QALY (Figure 3).

D I S C U S S I O N
This study aimed to assess the cost-effectiveness of HCV screening and risk reduction strategies among MSM living with HIV in France. Two key points may be drawn from this analysis. Firstly, risk reduction interventions have a strong potential to be efficient, with a 20% risk reduction intervention in the high-risk group being cost-saving compared with current practices. The efficiency of intensified HCV screening alone appears low. Secondly, combining a 20% risk reduction intervention with a 6-month HCV screening might be cost-effective compared with yearly screening (ICER = €61,389/QALY). While the French Health Authority has taken no official position with regard to a national WTP threshold, the per capita GDP (€33,270 in 2019 [38]) offers a point of departure to interpret our results, as others have previously done [39,40]. Using this basis of comparison, we might define a programme to be "cost-effective" if its ICER is less than three times the per capita GDP (€99,810), and "very cost-effective" if its ICER falls below the GDP (€33,270). In our analysis, screening every 6 months combined with risk reduction resulted in an ICER of about two times the French GDP. This strategy would not be considered as cost-effective with a WTP of one time the GDP, but would be regarded as cost-effective for a WTP threshold between €60,000 and €200,000 per QALY gained. Additionally, combining a 20% risk reduction intervention with a 6-month HCV screening provided a cost per infection averted of €37,790 compared with yearly screening. Although MSM engaged in high-risk practices drive the HCV epidemic, intensified screening every 3 months in this population (while screening the low-risk group every 6 months) was not cost-effective, even if we assumed no additional cost to identify high-risk persons. This suggests that the health gains offered by more frequent screening would not justify the additional costs.
Overall, HCV screening strategies had no impact on the number of LYs gained and a limited impact on the number of QALYs. Our results highlight that routine screening every year is an already favourable situation, especially when a high proportion of MSM living with HIV are engaged in care and rapidly treated once diagnosed. Moreover, since chronic HCV infection can progress slowly (20-30 years to cirrhosis [41,42]), the marginal benefit of screening more than once a year may be small in terms of morbidity and mortality. Although our model allows for progression to advanced disease, most persons with HCV who are already under HIV care progress no further than acute infection or fibrosis stage F0. This is particularly pertinent in France, where heightened awareness has led to decreasing HCV incidence, a low prevalence (3.62% in 2014) and comparatively few MSM in the most severe stages of HCV infection.
A few recently published studies used dynamic compartmental modelling to evaluate the cost-effectiveness of different HCV screening and treatment interventions among MSM living with HIV in the Netherlands [43,44], or among all MSM (not only those living with HIV) in the United Kingdom [45]. Popping et al. reported minimal QALY benefit from frequent HCV testing in Dutch MSM living with HIV [44]. However, the authors showed that a simplified HCV screening strategy using lower-cost but equally effective antigen tests (6monthly, targeted to MSM living with HIV with a previously known HCV infection) was cost-saving compared with current monitoring and testing strategies (based on PCR tests in case of elevated alanine aminotransferase or positive serological test). Our study contributes to the existing literature by simultaneously assessing both testing and risk reduction strategies and by identifying efficient combinations of both interventions among French MSM living with HIV.
This study has limitations. Firstly, uncertainties persist regarding the input data of the model. However, risk reduction targeted to the high-risk group remained cost-saving in all sensitivity analyses. Secondly, our model is specific to France where favourable circumstances prevail regarding HCV screening and treatment among MSM living with HIV. It might be useful to explore the generalizability of our findings to other settings. However, there is reason to believe that our conclusions regarding the efficiency of risk reduction strategies will apply to other high-income settings with similar HCV epidemics among MSM (i.e. decreasing incidence [46][47][48]). Engagement in chemsex and other high-risk sexual practices substantially contributes to HCV transmission among MSM living with HIV in all settings, and a number of modelling studies have shown that micro-elimination cannot be achieved without implementing risk reduction interventions [15,49,50]. Thirdly, our compartmental model design and homogeneous mixing assumption may be less appropriate for evaluating strategies targeted to specific populations, compared to an individual-based simulation and/or an assortative mixing preference between risk groups [51]. HCV screening every 6 months proved less cost-effective when we assumed assortative mixing, mostly because increased screening added less value to risk reduction. We may also have over-simplified the reality of risk-reduction programme delivery. While we assumed counselling sessions were dispensed by the medical staff for practicality, peer-counselling could be more relevant in this situation. There is, unfortunately, a paucity of data regarding risk reduction interventions aimed to reduce HCV transmission among MSM engaged in high-risk practices. Nevertheless, our aim was to provide valuable information on whether such strategies could be cost-effective. In addition, we assumed that all HCV transmission in MSM living with HIV in France was attributable to contacts within this population. Previous studies have described both an international network of HCV transmission among MSM living with HIV [52,53] and HCV infections among MSM without HIV infection receiving HIV pre-exposure prophylaxis (PrEP) [9,54]. However, we found no estimate of what proportion of HCV incidence among MSM living with HIV in France is attributable to contact with these other populations. It also remains unclear whether and how PrEP users could influence the dynamics of HCV infections among MSM living with HIV. For instance, PrEP prescription requires regular follow-up, providing more opportunities to be tested for HCV, which could contribute to reducing HCV incidence among both populations. Another modelling assumption was that all MSM living with HIV were equally likely to be diagnosed. Future research might consider heterogeneity in HIV screening rates among different MSM subgroups and the potential costs and benefits of interventions targeted to persons facing unusually high barriers to care. Finally, we cannot entirely rule out that current practices already tend towards 6-month HCV screening among MSM living with HIV in France. However, our results suggest that this might possibly be an optimal screening frequency.

C O N C L U S I O N S
In conclusion, the risk reduction was a critical intervention in our analysis, indicating the high value of targeting chemsex and other high-risk practices among MSM living with HIV in France. Thus, depending on policymakers' WTP, screening MSM living with HIV every 6 months for HCV might be considered as cost-effective, in combination with risk reduction.

C O M P E T I N G I N T E R E S T S
KC has received honoraria for presentations from Gilead outside of this work. VS reports lecture fees from Gilead, Janssen and Viiv outside the submitted work. JG reports personal fees from Merck, grants and personal fees from ViiV healthcare, grants and personal fees from Gilead Sciences, personal fees from Roche, personal fees from AstraZeneca, and personal fees from Janssen, outside the submitted work. SDB has received consultancy fees from Intercept. The remaining authors have nothing to disclose.

A C K N O W L E D G E M E N T S
We thank Isabelle Durand-Zaleski, Perrine Roux and David Michels for their suggestions and advice.

F U N D I N G
This work was supported by the French Agency for Research on AIDS and Viral Hepatitis (ANRS) [grant number 95031]. The ANRS had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

D ATA AVA I L A B I L I T Y S TAT E M E N T
Most of the data that support the findings of this study are available from the cited references and supplementary material. PREVAGAY 2015 data are available from the authors upon reasonable request and additional approval from Santé Publique France. Other data are available from the authors upon reasonable request. Anyone can submit a research project to the ANRS CO4-FHDH scientific committee and obtain access to the data after approval by the scientific committee. Applicants should use a standardized form available on the ANRS CO4-FHDH website (https://anrs-co4.fhdh.fr) to describe the context and objectives of the study. The scientific committee reviews the submitted projects twice a year. For successful applicants with adequate statistical expertise, the data can be transferred with French data protection agency CNIL approval; otherwise, the ANRS CO4 FHDH statistical centre analyses the data cooperatively with the applicant.
Anyone can submit a research project to Santé Publique France and obtain access to the routine HIV surveillance data after approval by the scientific committee, by writing to ANSP-DMI-VIC@santepubliquefrance.fr.

S U P P O R T I N G I N F O R M AT I O N
Additional information may be found under the Supporting Information tab for this article: Table S1. Model parameters values Table S2. Assumptions for HCV treatment uptake evolution among MSM living with HIV in France from 2014 to 2019 Table S3. Annual mean costs attributable to chronic hepatitis C: ambulatory costs (never treated and after HCV treatment failure) and hospitalization costs (no death and in-hospital death) [9] Table S4. Health-related utilities Table S5. Distributions used in the probabilistic sensitivity analysis Table S6. Description of costs, number of infections, and cost per infection averted for nondominated strategies on the efficiency frontier Table S7. Sensitivity analysis decreasing the efficacy of risk reduction strategies to 15% and 10% Table S8. Sensitivity analysis assuming a 98% SVR rate from 2019 for those treated before cirrhosis (i.e., acute infection and fibrosis stages F0, F1, F2, F3) Table S9. Sensitivity analysis assuming assortative mixing Figure S1. Flow diagrams of the HCV transmission and progression model.